Abstract
Metastasis is a critical factor contributing to poor prognosis in cancer, but the underlying mechanisms of metastasis are still poorly understood. We established a highly metastatic cell subline (HOC313-LM) derived from an oral squamous cell carcinoma cell line (HOC313) for uncovering the mechanisms of metastasis, and identified deoxyhypusine synthase (DHPS) as a metastasis-associated gene within the specific amplification at 19p13.2–p13.13 in HOC313-LM. DHPS-mediated hypusine-modification of eukaryotic translation factor 5A facilitated the translation of RhoA, resulting in the activation of the RhoA signaling pathway and leading to not only increased cell motility, invasion and metastasis of cancer cells in vitro, but also increased tumor growth in vivo. Moreover, the use of N1-Guanyl-1,7-diaminoheptane, a DHPS inhibitor, resulted in a significant decrease in tumor formation in vivo. In patients with esophageal squamous cell carcinoma (ESCC), overexpression of DHPS in ESCC tumors was significantly associated with worse recurrence-free survival, and correlated with distant metastasis. The elucidation of these molecular mechanisms within the hypusine cascade suggests opportunities for novel therapeutic targets in SCC.
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References
Nguyen DX, Bos PD, Massague J . Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 2009; 9: 274–284.
Giancotti FG . Mechanisms governing metastatic dormancy and reactivation. Cell 2013; 155: 750–764.
Wan L, Pantel K, Kang Y . Tumor metastasis: moving new biological insights into the clinic. Nat Med 2013; 19: 1450–1464.
Chiang AC, Massague J . Molecular basis of metastasis. N Engl J Med 2008; 359: 2814–2823.
Reymond N, d'Agua BB, Ridley AJ . Crossing the endothelial barrier during metastasis. Nat Rev Cancer 2013; 13: 858–870.
Park MH, Nishimura K, Zanelli CF, Valentini SR . Functional significance of eIF5 A and its hypusine modification in eukaryotes. Amino Acids 2010; 38: 491–500.
Gutierrez E et al. eIF5 A promotes translation of polyproline motifs. Mol Cell 2013; 51: 35–45.
Kaiser A . Translational control of eIF5 A in various diseases. Amino Acids 2012; 42: 679–684.
Huang Y, Higginson DS, Hester L, Park MH, Snyder SH . Neuronal growth and survival mediated by eIF5 A, a polyamine-modified translation initiation factor. Proc Natl Acad Sci USA 2007; 104: 4194–4199.
Lee NP, Tsang FH, Shek FH, Mao M, Dai H, Zhang C et al. Prognostic significance and therapeutic potential of eukaryotic translation initiation factor 5A (eIF5A) in hepatocellular carcinoma. Int J Cancer 2010; 127: 968–976.
Preukschas M, Hagel C, Schulte A, Weber K, Lamszus K, Sievert H et al. Expression of eukaryotic initiation factor 5A and hypusine forming enzymes in glioblastoma patient samples: implications for new targeted therapies. PLoS One 2012; 7: e43468.
Caraglia M, Park MH, Wolff EC, Marra M, Abbruzzese A . eIF5A isoforms and cancer: two brothers for two functions? Amino Acids 2013; 44: 103–109.
Tunca B, Tezcan G, Cecener G, Egeli U, Zorluoglu A, Yilmazlar T et al. Overexpression of CK20, MAP3K8 and EIF5A correlates with poor prognosis in early-onset colorectal cancer patients. J Cancer Res Clin Oncol 2013; 139: 691–702.
Lu Z, Song Q, Yang J, Zhao X, Zhang X, Yang P et al. Comparative proteomic analysis of anti-cancer mechanism by periplocin treatment in lung cancer cells. Cell Physiol Biochem 2014; 33: 859–868.
Fujimura K, Wright T, Strnadel J, Kaushal S, Metildi C, Lowy AM et al. A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic cancer. Cancer Res 2014; 74: 6671–6681.
Scuoppo C, Miething C, Lindqvist L, Reyes J, Ruse C, Appelmann I et al. A tumour suppressor network relying on the polyamine-hypusine axis. Nature 2012; 487: 244–248.
Taylor CA, Zheng Q, Liu Z, Thompson JE . Role of p38 and JNK MAPK signaling pathways and tumor suppressor p53 on induction of apoptosis in response to Ad-eIF5A1 in A549 lung cancer cells. Mol Cancer 2013; 12: 35.
Wang FW, Guan XY, Xie D . Roles of eukaryotic initiation factor 5A2 in human cancer. Int J Biol Sci 2013; 9: 1013–1020.
Tang DJ, Dong SS, Ma NF, Xie D, Chen L, Fu L et al. Overexpression of eukaryotic initiation factor 5A2 enhances cell motility and promotes tumor metastasis in hepatocellular carcinoma. Hepatology 2010; 51: 1255–1263.
Li Y, Fu L, Li JB, Qin Y, Zeng TT, Zhou J et al. Overexpression of EIF5A2 promotes colorectal carcinoma cell aggressiveness by upregulating MTA1 through C-myc to induce epithelial-mesenchymaltransition. Gut 2012; 61: 562–575.
Zhu W, Cai MY, Tong ZT, Dong SS, Mai SJ, Liao YJ et al. Increased expression of EIF5A2, via hypoxia or gene amplification, contributes to metastasis and angiogenesis of esophageal squamous cell carcinoma. Gastroenterology 2014; 146: 1701–13.e9.
Zender L, Xue W, Zuber J, Semighini CP, Krasnitz A, Ma B et al. An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer. Cell 2008; 135: 852–864.
Guan XY, Fung JM, Ma NF, Lau SH, Tai LS, Xie D et al. Oncogenic role of eIF-5A2 in the development of ovarian cancer. Cancer Res 2004; 64: 4197–4200.
Wei JH, Cao JZ, Zhang D, Liao B, Zhong WM, Lu J et al. EIF5A2 predicts outcome in localised invasive bladder cancer and promotes bladder cancer cell aggressiveness in vitro and in vivo. Br J Cancer 2014; 110: 1767–1777.
Maier B, Ogihara T, Trace AP, Tersey SA, Robbins RD, Chakrabarti SK et al. The unique hypusine modification of eIF5A promotes islet beta cell inflammation and dysfunction in mice. J Clin Invest 2010; 120: 2156–2170.
Memin E, Hoque M, Jain MR, Heller DS, Li H, Cracchiolo B et al. Blocking eIF5A modification in cervical cancer cells alters the expression of cancer-related genes and suppresses cell proliferation. Cancer Res 2014; 74: 552–562.
Dong Z, Arnold RJ, Yang Y, Park MH, Hrncirova P, Mechref Y et al. Modulation of differentiation-related gene 1 expression by cell cycle blocker mimosine, revealed by proteomic analysis. Mol Cell Proteomics 2005; 4: 993–1001.
Balabanov S, Gontarewicz A, Ziegler P, Hartmann U, Kammer W, Copland M et al. Hypusination of eukaryotic initiation factor 5A (eIF5A): a novel therapeutic target in BCR-ABL-positive leukemias identified by a proteomics approach. Blood 2007; 109: 1701–1711.
Lou B, Fan J, Wang K, Chen W, Zhou X, Zhang J et al. N1-guanyl-1,7-diaminoheptane (GC7) enhances the therapeutic efficacy of doxorubicin by inhibiting activation of eukaryotic translation initiation factor 5A2 (eIF5A2) and preventing the epithelial-mesenchymal transition in hepatocellular carcinoma cells. Exp Cell Res 2013; 319: 2708–2717.
Eberhard Y, McDermott SP, Wang X, Gronda M, Venugopal A, Wood TE et al. Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells. Blood 2009; 114: 3064–3073.
Jasiulionis MG, Luchessi AD, Moreira AG, Souza PP, Suenaga AP, Correa M et al. Inhibition of eukaryotic translation initiation factor 5A (eIF5A) hypusination impairs melanoma growth. Cell Biochem Funct 2007; 25: 109–114.
Iden S, Collard JG . Crosstalk between small GTPases and polarity proteins in cell polarization. Nat Rev Mol Cell Biol 2008; 9: 846–859.
Karlsson R, Pedersen ED, Wang Z, Brakebusch C . Rho GTPase function in tumorigenesis. Biochim Biophys Acta 2009; 1796: 91–98.
Pickering CR, Zhang J, Yoo SY, Bengtsson L, Moorthy S, Neskey DM et al. Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov 2013; 3: 770–781.
Lin DC, Hao JJ, Nagata Y, Xu L, Shang L, Meng X et al. Genomic and molecular characterization of esophageal squamous cell carcinoma. Nat Genet 2014; 46: 467–473.
Song Y, Li L, Ou Y, Gao Z, Li E, Li X et al. Identification of genomic alterations in oesophageal squamous cell cancer. Nature 2014; 509: 91–95.
Villalonga P, Ridley AJ . Rho GTPases and cell cycle control. Growth Factors 2006; 24: 159–164.
Chan CH, Lee SW, Li CF, Wang J, Yang WL, Wu CY et al. Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis. Nat Cell Biol 2010; 12: 457–467.
Fujimura K, Choi S, Wyse M, Strnadel J, Wright T, Klemke R . Eukaryotic translation initiation factor 5A (EIF5A) regulates pancreatic cancer metastasis by modulating RhoA and Rho-associated kinase (ROCK) protein expression levels. J Biol Chem 2015; 290: 29907–29919.
Mandal A, Mandal S, Park MH . Genome-wide analyses and functional classification of proline repeat-rich proteins: potential role of eIF5A in eukaryotic evolution. PLoS One 2014; 9: e111800.
Semenza GL . Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 4: 191–196.
Tam WL, Weinberg RA . The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 2013; 19: 1438–1449.
Zender L, Spector MS, Xue W, Flemming P, Cordon-Cardo C, Silke J et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 2006; 125: 1253–1267.
Shih IeM, Nakayama K, Wu G, Nakayama N, Zhang J, Wang TL . Amplification of the ch19p13.2 NACC1 locus in ovarian high-grade serous carcinoma. Mod Pathol 2011; 24: 638–645.
Yap KL, Fraley SI, Thiaville MM, Jinawath N, Nakayama K, Wang J et al. NAC1 is an actin-binding protein that is essential for effective cytokinesis in cancer cells. Cancer Res 2012; 72: 4085–4096.
Nakayama K, Nakayama N, Davidson B, Sheu JJ, Jinawath N, Santillan A et al. A BTB/POZ protein, NAC-1, is related to tumor recurrence and is essential for tumor growth and survival. Proc Natl Acad Sci USA 2006; 103: 18739–18744.
Neeb A, Wallbaum S, Novac N, Dukovic-Schulze S, Scholl I, Schreiber C et al. The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of colorectal cancer patients. Oncogene 2012; 31: 3796–3806.
Straume O, Shimamura T, Lampa MJ, Carretero J, Oyan AM, Jia D et al. Suppression of heat shock protein 27 induces long-term dormancy in human breast cancer. Proc Natl Acad Sci USA 2012; 109: 8699–8704.
Cipollini G, Berti A, Fiore L, Rainaldi G, Basolo F, Merlo G et al. Down-regulation of the nm23.h1 gene inhibits cell proliferation. Int J Cancer 1997; 73: 297–302.
He X, Zheng Z, Li J, Ben Q, Liu J, Zhang J et al. DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/ERK/uPA. Carcinogenesis 2012; 33: 555–562.
Casero RA Jr, Marton LJ . Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat Rev Drug Discov 2007; 6: 373–390.
Zhou H, Shen T, Luo Y, Liu L, Chen W, Xu B et al. The antitumor activity of the fungicide ciclopirox. Int J Cancer 2010; 127: 2467–2477.
Minden MD, Hogge DE, Weir SJ, Kasper J, Webster DA, Patton L et al. Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies. Am J Hematol 2014; 89: 363–368.
Yasumoto E, Nakano K, Nakayachi T, Morshed SR, Hashimoto K, Kikuchi H et al. Cytotoxic activity of deferiprone, maltol and related hydroxyketones against human tumor cell lines. Anticancer Res 2004; 24: 755–762.
Muramatsu T, Imoto I, Matsui T, Kozaki K, Haruki S, Sudol M et al. YAP is a candidate oncogene for esophageal squamous cell carcinoma. Carcinogenesis 2011; 32: 389–398.
Ono H, Imoto I, Kozaki K, Tsuda H, Matsui T, Kurasawa Y et al. SIX1 promotes epithelial-mesenchymal transition in colorectal cancer through ZEB1 activation. Oncogene 2012; 31: 4923–4934.
Acknowledgements
This study was supported in part by a Grant-in Aid for Scientific Research (KAKENHI) for Innovative Areas (22134002, 15H05908) (Integrative Systems Understanding of Cancer for Advanced Diagnosis, Therapy and Prevention), Scientific Research (A) (22240090, 25250019), Challenging Exploratory Research (B) (15K18401), Research Activity Start-up (26890012), JSPS Fellows from Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Tailor-Made Medical Treatment with the BioBank Japan Project (BBJ) and the Practical Research for Innovative Cancer Control (15Ack0106017h0002) from Japan Agency for Medical Research and development, AMED and Global Center of Excellence (GCOE) Program for International Research Center for Molecular Science in Tooth and Bone Diseases, from the Ministry of Education, Culture, Sports, Science and Technology, Japan. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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Muramatsu, T., Kozaki, Ki., Imoto, S. et al. The hypusine cascade promotes cancer progression and metastasis through the regulation of RhoA in squamous cell carcinoma. Oncogene 35, 5304–5316 (2016). https://doi.org/10.1038/onc.2016.71
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DOI: https://doi.org/10.1038/onc.2016.71
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